Gender Disparities in Hypertensive Emergency Admissions: A National Retrospective Cohort Study

Background Hypertension is one of the most common conditions affecting almost one in every five adults globally and hypertensive emergency is a life-threatening complication of uncontrolled hypertension leading to significant disability. Despite advances in treatment, gender disparities are yet to be addressed. Methods This retrospective cohort study used nationally representative data from the Healthcare Cost and Utilization Project (HCUP), specifically the National Inpatient Sample, to study two cohorts divided by sex (males and females). The primary outcome was all-cause inpatient mortality. Multivariate logistic regression analysis yielded adjusted odds ratios (aORs) for confounders. Secondary outcomes included length of stay (LOS) and total hospital charges. Multivariate linear regression identified independent predictors. We described crude rates of mechanical ventilation, acute kidney injury (AKI) requiring hemodialysis (HD), and vasopressor requirements. Patient demographics were also presented. We used the chi-squared (χ2) test for categorical variables and Student's t-test for continuous variables. Statistical significance was defined as a two-tailed p-value<0.05. Results A total of 229,025 patients met the inclusion criteria, where 52% were male and 48% were female. The mean patient age was 58 years (55 for men and 62 for women, p <0.001). White patients represented 40% of hospitalizations (males: 37%; females: 42%), black patients represented 42% (males: 43%; females: 41%), and Hispanics 11% (males: 12%; females: 10%). Medicare was the primary payer 47% of the time (males: 38%; females: 56%), Medicaid in 21% (males: 23%; females: 18%), private insurance in 20% (males: 23%; females: 17%), and no insurance in 10% (males: 14%; females: 7%). Female patients had higher rates of chronic obstructive pulmonary disease (COPD) (21% for females vs. 15% for males), connective tissue disease (4.6% for females vs. 0.98% for males; p<0.001), and dementia (6% for females vs. 3% for males). Conversely, males had a higher rate of chronic kidney disease (CKD) (51% vs. 42% for females). Male sex was a predictor of mortality (aOR 1.39, p=0.036), along with age (aOR 1.02, p<0.001) and Charlson Comorbidity Index (http://mchp-appserv.cpe.umanitoba.ca/viewConcept.php?printer=Y&conceptID=1098) (aOR 1.20, p<0.001). Sex was not a predictor of length of stay (LOS) (p=0.496) or total hospital charges (p=0.192). Conclusions In an attempt to achieve better outcomes in patients affected by hypertensive emergency, our retrospective cohort study found that male patients who experienced hypertensive emergency had 39% higher odds of mortality than female patients. Age and Charlson Comorbidity Index were additionally found to be independent predictors of mortality.


Introduction
According to the World Health Organization (WHO), hypertension affects 1.28 billion people globally, with 46% of them unaware of their condition, and only one in five people with hypertension having their blood pressure under control [1]. In the United States, the Center for Disease Control and Prevention (CDC) defines hypertension as having a systolic blood pressure greater than 130 mmHg or diastolic blood pressure greater than 80 mmHg. According to their estimates, 47% of the adult population in the United States has hypertension [2].
A hypertensive emergency is a serious complication that can arise due to prolonged and uncontrolled hypertension, triggered by non-adherence to prescribed treatment leading to an abrupt surge in blood pressure, resulting in acute damage to vital organs which may lead to long-term disability or chronic morbidity. Hypertensive emergencies encompass severe conditions, such as hemorrhagic stroke, ischemic stroke, myocardial infarction, acute heart failure, and other debilitating diseases requiring immediate medical attention for proper management and care-taking measures. The consequences stemming from hypertensive emergencies are significant acutely and have substantial long-term ramifications on patients' well-being and quality of life if left untreated or inadequately managed over time [3][4][5].
The risk factors for hypertensive emergencies include being Caucasian, older, and having a sedentary lifestyle, among others [6]. Currently, there is limited knowledge regarding the potential gender differences in patients diagnosed with a hypertensive emergency, and further academic exploration and research are required to gain a more comprehensive understanding of this topic. The available literature on hypertensive emergency patients falls short of fully exploring potential gender disparities. Therefore, there is a pressing need for more rigorous academic inquiry and empirical research to investigate this subject matter comprehensively. Despite numerous epidemiological studies, there is a lack of research examining the impact of sex on outcomes, with conflicting data on whether male patients have a higher mortality rate.
Therefore, our study aimed to address this gap and investigate gender disparities in-hospital mortality. We also examined whether sex affected hospital length of stay, total charges, the need for hemodialysis and mechanical ventilation, and the prevalence of common comorbidities.

Data source
This retrospective cohort study utilized the National Inpatient Database, which is the largest publicly available inpatient database in the United States. The database has been available since 1988 as part of the Healthcare Cost and Utilization Project (HCUP) sponsored by the Agency for Healthcare Research and Quality (AHRQ). It includes data from 48 states plus the District of Columbia, comprising over seven million in-hospital stays annually. Long-term acute-care hospitals and rehabilitation centers were excluded from the study, and data from five years (2016-2020) were obtained. The study examined several variables, including age, sex, race, and length of stay. Diagnoses were coded using the International Classification of Diseases, 10th revision (ICD-10). The study did not include individually identifiable health information, and discharge weights were provided to facilitate the production of national estimates. Therefore, all values presented in the study are weighted estimates. The study adhered to data use agreement regulations following completed training to ensure patient privacy and confidentiality. Overall, the use of the National Inpatient Database provided a robust and comprehensive source of data for our study, allowing for the examination of large-scale trends and outcomes in patients with various medical conditions.

Study population
This study utilized billable codes from the ICD-10 to identify patients admitted for hypertensive emergency from January 2016 to December 2020. The study was limited to non-elective admissions of patients aged 18 years and older, and younger patients were excluded. Patient and hospital characteristics were identified using the National Inpatient Database (NIS) variables. To comply with the HCUP data use agreement, variables with less than 10 observations were excluded from the analysis. This study utilized a rigorous approach to identify and include only relevant patient populations in the analysis, ensuring the accuracy and validity of the results.

Missing data
In this study, missing data on variables of interest, including race, death, elective admission, female sex, insurance, total charges, and income, were observed in a small percentage of cases, with rates ranging from 0.01% to 3.4% in 2020. These rates were comparable to those of previous years, except for race in 2016, which had a higher rate of missing data (5.4%). To maintain data integrity and ensure the accuracy of the results, hospitalizations with missing data were excluded from the analysis. The study employed a rigorous approach to address missing data, minimizing its impact on the analysis and conclusions.

Study outcomes
In this study, our primary outcome was mortality, which we defined as in-hospital mortality during admission. Our secondary outcomes were the length of stay (LOS) and total hospital cost, defined as the number of days from admission to discharge or death and the total cost of hospitalization in USD, respectively. Additionally, we described the prevalence of common comorbidities and requirements for mechanical ventilation (MV), continuous renal replacement therapy (CRRT), and acute kidney injury requiring hemodialysis. We divided the studied group into two following cohorts based on gender: males and females.

Statistical analysis
The statistical analysis of the data collected in this study was performed using the STATA MP/17 version (College Station, TX: StataCorp). Initially, we identified the number of patients who fulfilled the inclusion criteria and recorded their baseline demographic and hospital characteristics. The primary outcome of this study was all-cause mortality, which we analyzed using multivariate logistic regression to adjust for confounding variables. The secondary outcomes of the study were the length of stay (LOS) and total hospital charges, which we analyzed using multivariate linear regression. We employed the chi-squared test to assess categorical variables, while continuous variables were analyzed using Student's t-test. Statistical significance was determined as a two-tailed P-value of less than 0.05.

Patient confidentiality and institutional board review
The HCUP databases consist of limited datasets, which are healthcare data from which 16 direct identifiers have been removed in accordance with the privacy rule. Based on the HIPAA privacy rule at 45 CFR (https://www.ecfr.gov/current/title-45), limited datasets are exempt from Institutional Review Board (IRB) oversight. The present study adhered to the principles outlined in the World Medical Association (WMA) Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethicalprinciples-for-medical-research-involving-human-subjects/) regarding the ethical conduct of research involving human subjects, particularly with respect to patient confidentiality.

Patient characteristics
The study sample was composed of 229,025 admissions that were identified over five years. A total of 120,326 males (52.51%) and 108,698 females (47.49%), with a mean age of 58 years were present (males 55 vs. females 62, p<0.001). The patient population was predominantly White (40.1%), followed by Black (42.57%), Hispanic (11.3%), Asian/PI (2.63%), and Native American (0.52%); differences between males and females were statistically significant (p<0.001) but not substantial enough to draw conclusions. The majority of patients were insured by Medicare, accounting for 47.72% of the total, followed by Medicaid (21.06%), private insurance (20.39%), and no insurance (10.82%). Statistically significant differences were observed between males and females (p<0.001), with females having a higher percentage of Medicare coverage and males having a higher percentage of private insurance. Regionally, the study population was evenly distributed across the Midwest (20.86%), Northeast (16.22%), South (47.4%), and West (15.52%). The Charlson Comorbidity Index (CCI) was used to measure comorbidity, with a CCI score of 0 observed in 13.85% of the sample, while a CCI score of 3 or greater was seen in 50.64% of patients. Differences between males and females were statistically significant (p<0.001), with females having a higher percentage of CCI scores greater than or equal to 3. The mean hospital LOS was 3.5 days (p=0.467), and the mean total hospital charges were $42,247 (p=0.002). Table 1 shows the patient characteristics.

Associated conditions and complications during hospitalizations
Overall, there are several notable differences between males and females regarding the prevalence of certain conditions and complications during hospitalizations. For example, females had a significantly higher prevalence of connective tissue disease, diabetes with and without complications, dementia, cerebrovascular accident, and chronic obstructive pulmonary disease (COPD). On the other hand, males had a significantly higher prevalence of metastatic cancer and AIDS. It is also worth noting that there were several conditions where there were no significant differences between males and females. These include mechanical ventilation, acute kidney injury (AKI) requiring hemodialysis, moderate-to-severe liver disease, hemiplegia, peptic ulcer, and peripheral vascular disease.

Predictors of mortality
Males had significantly higher odds of mortality than females (aOR=1.39, 95% CI=1.02-1.91, p=0.036). Age was also a significant predictor of mortality, with each additional year increasing the odds of mortality by a factor of 1.02 (95% CI=1.01-1.04, p<0.001). The Charlson Comorbidity Index was also a significant predictor of mortality, with each additional point in the index increasing the odds of mortality by a factor of 1.20 (95% CI=1.13-1.28, p<0.001). Race, location, or teaching status did not impact mortality (p>0.05). Table 3 demonstrates predictors of mortality.

Predictors of length of stay
Age, with a coefficient of 0.004 indicates that the length of stay increases by 0.004 days for each one-year increase in age, and this effect is statistically significant (p=0.002). CCI has a coefficient of 0.427, indicating that patients with a higher Charlson Comorbidity Index score have a longer length of stay. This effect is statistically significant (p<0.001). The location/teaching status of the hospital is also a significant predictor of length of stay. Patients in urban teaching hospitals have the longest length of stay, with a coefficient of 0.509, followed by those in urban non-teaching hospitals (coefficient of 0.169). Patients in rural hospitals have the shortest length of stay (reference group). These effects are statistically significant, with p-values of <0.001 for urban teaching hospitals and 0.022 for urban non-teaching hospitals. Table 4 demonstrates predictors of length of stay.

Predictors of hospital costs
The mean total hospitalization cost was $42,247. Hispanic or Asian/Pacific Islander races, being treated at an urban non-teaching or urban teaching hospital, and having a higher Charlson Comorbidity Index score are all associated with higher healthcare costs, on average (p<0.05). Table 5 shows the predictors of cost.

Discussion
Worldwide, hypertension is a major health challenge, and despite groundbreaking advancements in its management, uncontrolled hypertension is still a major cause of hospitalization in the United States of America [7]. Moreover, as a result, we witness hypertensive crises secondary to suboptimally controlled blood pressure. Hypertensive emergency and urgency are two types of hypertensive crisis. A hypertensive emergency is characterized by the presence of target organ damage, which is not a case of hypertensive urgency [8]. With hypertensive emergencies being a major cause of morbidity in the United States affecting both genders, having a better understanding of the gender disparities is the main aim of our study.
In our study, we found 120,326 males (52.51%) and 108,698 females (47.49%), with a mean age of 58 (males 55 vs. females 62 years, p <0.001). Similar results were observed in another study using National Inpatient Database (NIS), which might be explained by the higher comorbid conditions in men than women [9]. In that study, it was also observed that men admitted with hypertensive crises were younger than women, which might be due to the fact that blood pressure control worsens in women as they grow older [9], which is linked to hormone changes [10,11]. On the contrary, one study found that female patients were 2.494 times more likely to develop hypertensive emergencies than males (95% CI: 1.111-5.596). However, in that study, more than half of the study population were females [12]. However, another study conducted also observed that the female sex was associated with increased incidences of hypertensive crisis, which might have been a result of less understanding of hypertension-related cardiovascular complications in women [13].
Male sex was a predictor of mortality (aOR 1.39, p=0.036) as per our study. One reason behind this finding is the presence of multiple comorbidities in men that make them more prone to fatal outcomes (Charlson Comorbidity Index with p<0.001). In one study, old age, male sex, history of chronic kidney disease, and proteinuria were listed as risk factors for mortality in hypertensive patients [14]. Individuals with chronic kidney disease were found to be at increased risk of all-cause mortality secondary to hypertensive emergency [14]. Furthermore, as observed in our study, males had a higher rate of CKD (51% vs. 42% for females). Additionally, one article found that the diagnosis of hypertension is more common in women [15]. However, the incidence of hypertensive emergencies is more common in men, indicating that hypertensive men are more likely to suffer from end-organ damage [15]. Moreover, as we all know, estrogen (E2) is cardioprotective (increasing angiogenesis and vasodilation and decreasing reactive oxygen species, oxidative stress, and fibrosis) and plays a crucial role in regulating vasorelaxation, vasoconstriction, and endothelial function through endothelial Nitric Oxide Synthase dependent mechanisms. This mechanism also reduces hypertrophy on the vascular wall and increases cardiac function in hypertensive rat models. Stimulating estrogen receptors have also been shown to attenuate hypertension by reducing the expression of angiotensin-converting enzyme, levels of angiotensin II, and vasoconstriction [10]. Therefore females have better outcomes despite suffering from hypertension.
Age has been proven to be a risk factor for hypertensive emergencies. For example, one study found that the most common age group afflicted is 60-80 years [6]. In other studies, the mean age was in the fifth decade of life [16][17][18]. We observe this finding as one of the most important mechanisms to regulate blood pressure (BP); systemic vascular resistance (SVR) is increased in the elderly resulting in elevated BP. This increase in SVR is secondary to endothelial dysfunction, neuro-hormonal dysregulation, and a reduction in renal homeostatic mechanisms due to decreased glomerular filtration rate [17,[19][20][21]. As a result, BP control is a bigger challenge in the elderly, leading to uncontrolled HTN, hypertensive crises, and complications.

Limitations
Our study has many strengths, such as a large sample of patients, using the National Inpatient Sample, and proper confounders variables were addressed using logistic variables regression; furthermore, the first study addressed the lack of evidence in hypertensive crises in gender disparities. However, it also has limitations; diagnoses have been collected using the ICD-10 coding system; also, just diagnosis discharges are taken into consideration and analyzed; therefore, secondary diagnoses were not included making it impossible to know if secondary diagnosis played an essential role in outcomes. Moreover, the treatment used is unavailable (NIS lacked this data); due to the nature of the data used, it was impossible to decipher if the same patient had multiple hospitalizations, which could potentially skew the data.

Conclusions
In this retrospective cohort study, utilizing national representative data over five years, it was found that males exhibited significantly higher odds of mortality than females. Furthermore, the study identified age and CCI as independent predictors of mortality. These findings have significant implications for healthcare providers and policymakers alike. Healthcare providers should be mindful of the elevated mortality risk among male patients and may need to adopt distinct treatment approaches for male and female patients. Policymakers can also utilize these findings to inform the development of targeted public health initiatives to reduce mortality rates, particularly among at-risk groups.